CSF single cell transcriptomic changes associated with post-acute sequelae of SARS CoV 2 infection

Natural history and mechanisms for persistent cognitive symptoms (also known as “brain fog”) following acute and often mild COVID-19 are unknown. In a large prospective cohort of people who recovered from acute COVID-19 in the New York City/New Jersey area, we found the presence of cognitive dysfunction to closely associate with fatigue symptoms and, in some people, brain imaging abnormalities. In a smaller subset of people who underwent cerebrospinal fluid analysis at a median of 9 months after their initial infection, there was no evidence to suggest changes related to Alzheimer’s disease or neurodegeneration. However, single cell gene expression analysis of immune cells (T cells, border associated macrophages, microglia-like myeloid cells, myeloid dendritic cells) from the cerebrospinal fluid showed many changes seen in models of acute SARS-CoV-2 infection. Longitudinal follow-up additionally showed recovery from cognitive dysfunction to be very slow, and associate with greater – not less – activation of interferon-related inflammatory processes in both single cell transcriptomic and targeted fluid proteomic studies. These findings suggest persistent brain fog following COVID-19 to resemble more viral infection than autoimmune disorders. We performed a cross-sectional comparison between people who are healthy control (HC) subjects and people who developed cognitive symptoms after COVID-19 with (PASC with Cognitive Impairment, PASC-CI) or without (PASC with Subjective Cognitive Concerns, PASC-SCC) objective cognitive deficits. We further compared CSF scRNASeq between people with PASC-CI who later recovered and people with PASC-CI whose deficits persisted.